Research ArticleCancer

Akt and ERK Control the Proliferative Response of Mammary Epithelial Cells to the Growth Factors IGF-1 and EGF Through the Cell Cycle Inhibitor p57Kip2

Sci. Signal.  06 Mar 2012:
Vol. 5, Issue 214, pp. ra19
DOI: 10.1126/scisignal.2001986

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Checks and Balances

Growth factors stimulate various downstream pathways to engage the cell cycle and promote cell proliferation. Two of these pathways, the Akt pathway and the ERK pathway, are commonly used as indicators of proliferative or oncogenic signaling. Noting that the Akt and ERK pathways not only can sometimes act synergistically with each other but also can suppress each other’s signaling, Worster et al. explored their involvement in the proliferative response to insulin, insulin-like growth factor 1 (IGF-1), and epidermal growth factor (EGF). Insulin or IGF-1 failed to stimulate the proliferation of mammary epithelial cells independently of EGF but enhanced the response to EGF, whereas EGF stimulated proliferation in the absence of insulin or IGF-1. Activation of the Akt pathway in the absence of ERK activity by IGF-1 or insulin led to an increase in the abundance of the cell cycle inhibitor p57 and proliferative arrest. Concurrent ERK signaling suppressed this increase in p57, enabling proliferation to occur, and p57 depletion enabled IGF-1–induced proliferation in the absence of EGF. Thus, p57 acted as a network sensor capable of detecting and limiting the proliferative response to aberrant signaling states in which the Akt pathway was activated in isolation.